A CB1 receptor neutral antagonist reduced nicotine and THC self-administration and relapse in monkeys with fewer expected side effects than rimonabant, pointing to a potential dual-addiction treatment.
Read this if you are interested in pharmacological approaches to treating tobacco and cannabis addiction simultaneously.
New CB1 neutral antagonist matched rimonabant's anti-addiction effects for both nicotine and THC without affecting food reward.
What the researchers found
Researchers compared two types of CB1 receptor blockers in squirrel monkeys: rimonabant (an inverse agonist that was withdrawn from the market due to psychiatric side effects) and AM4113 (a newer neutral antagonist).
Both compounds reduced nicotine and THC self-administration and prevented relapse triggered by drug cues or priming doses. Neither compound affected cocaine or food-motivated behavior, demonstrating selectivity for cannabinoid and nicotine reward.
However, both rimonabant and AM4113 did reduce cue-induced relapse for cocaine, suggesting endocannabinoid involvement in how drug-associated cues trigger craving across different drugs.
The key clinical implication is that neutral antagonists like AM4113 may provide the addiction-reducing benefits of rimonabant without the depression and anxiety side effects that led to rimonabant's withdrawal from the market.
Why it matters
Tobacco and cannabis are the two most commonly used addictive substances worldwide. A single medication that could reduce both addictions simultaneously would be enormously valuable. Rimonabant showed this potential but was too dangerous. Neutral antagonists may preserve the benefit while eliminating the psychiatric risk.
The numbers in context
Both rimonabant and AM4113 reduced nicotine and THC self-administration. Neither affected cocaine or food reinforcement. Both reduced cue-induced reinstatement across all drug types. AM4113 is expected to have fewer psychiatric side effects than rimonabant.
How the study worked
Squirrel monkey study using intravenous self-administration paradigms for nicotine, THC, and cocaine. Researchers measured maintenance of drug-taking behavior and reinstatement of drug-seeking after extinction (modeling relapse). Both rimonabant and AM4113 were tested against each drug and food reinforcement.
What this study cannot tell us
Primate self-administration studies have good translational value but are not human clinical trials. AM4113 has not been tested in humans. The assumption that neutral antagonists will have fewer psychiatric side effects than inverse agonists has not been clinically confirmed. The sample size was small (typical for primate studies).
How to read the evidence
Moderate evidence from controlled primate studies using validated self-administration paradigms, with strong translational relevance but no human data yet.
When this study was published
Published in 2016. Development of CB1 neutral antagonists for addiction treatment continues in preclinical stages.
The bigger picture
The failure of rimonabant was a major setback for cannabinoid-based addiction medicine. This study reignites the approach by showing that a mechanistically different type of CB1 blocker (neutral antagonist vs inverse agonist) can achieve the same anti-addiction effects. The finding that cue-induced relapse involves endocannabinoid signaling across different drugs suggests the endocannabinoid system plays a broad role in how environmental triggers drive drug seeking.
Questions still open
- Will AM4113 or similar neutral antagonists be safe in human clinical trials? Could these compounds help with other addictions beyond tobacco and cannabis? Is the absence of food-reinforcement effects maintained at all doses, ensuring the compound would not cause appetite loss?
Common questions
Why was rimonabant taken off the market?
How is a neutral antagonist different?
Read the original research
Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(9), 2283-93
Citation
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana. (2016). Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(9), 2283-93. https://doi.org/10.1038/npp.2016.27
Explore the wider topic
- Physical vs Psychological Cannabis Dependence: What Science Actually Shows
- The Gap Between Cannabis Perception and Science: Why What We Believe Outpaces What We Know
- Cannabis Use Disorder: Am I Addicted? Self-Assessment Guide
- Cross-Addiction After Quitting Weed: When One Habit Replaces Another
- Is Weed Addictive? What the Research Actually Shows
- Is Cannabis Addictive? What the DSM-5 and Brain Science Say
- Quitting Weed and Alcohol Together: What to Know About Dual Cessation
- Is Rehab Necessary for Weed? An Honest Assessment
- Signs You May Have Cannabis Use Disorder: An Honest Self-Assessment
- Weed Vape Pen Addiction: Why Vaping Makes It Harder to Quit